Most vaccines are administered by intramuscular (IM) or subcutaneous (SC) routes, however, intradermal (ID) and transcutaneous (TC) techniques are regaining popularity. We will discuss in this review several factors that strongly justify the use of the cutaneous tissues and development of alternative methods for vaccination. That includes (1) our improved knowledge of skin physiology and better understanding of the barrier role of the horny layer, (2) the rationalization for targeting the different cutaneous layers, i.e. the epidermis, dermis, or hypodermis, (3) our advances in knowledge of the skin immune system, especially the plasticity of antigen-presenting cells (APCs) (i.e Langerhans cells (LC), dermal dendritic cells (DDC) and dermal macrophages) in the induction of immune responses, (4) the reduction of antigenic dose for some modes of cutaneous administration, (5) the increased need in needlefree vaccination strategies for developing countries to cope with blood contamination issues. Progress in skin immunization methods and better understanding of skin immunity allow proposing innovative and efficient vaccination strategies against infectious diseases.

Current conventional vaccination approaches do not induce potent CD8 T-cell responses for fighting mostly variable viral diseases such as influenza, avian influenza viruses or HIV. Following our recent study on vaccine penetration by targeting of vaccine to human hair follicular ducts surrounded by Langerhans cells, we tested in the first randomized Phase-Ia trial based on hair follicle penetration (namely transcutaneous route) the induction of virus-specific CD8 T cell responses. We chose the inactivated influenza vaccine – a conventional licensed tetanus/influenza (TETAGRIP®) vaccine – to compare the safety and immunogenicity of transcutaneous (TC) versus IM immunization in two randomized controlled, multi-center Phase I trials including 24 healthy-volunteers and 12 HIV-infected patients. Vaccination was performed by application of inactivated influenza vaccine according to a standard protocol allowing the opening of the hair duct for the TC route or needle-injection for the IM route. We demonstrated that the safety of the two routes was similar. We showed the superiority of TC application, but not the IM route, to induce a significant increase in influenza-specific CD8 cytokine-producing cells in healthy-volunteers and in HIV-infected patients. However, these routes did not differ significantly for the induction of influenza-specific CD4 responses, and neutralizing antibodies were induced only by the IM route. The CD8 cell response is thus the major immune response observed after TC vaccination. This Phase Ia clinical trial (Manon05) testing an anti-influenza vaccine demonstrated that vaccines designed for antibody induction by the IM route, generate vaccine-specific CD8 T cells when administered transcutaneously. These results underline the necessity of adapting vaccination strategies to control complex infectious diseases when CD8 cellular responses are crucial. Our work opens up a key area for the development of preventive and therapeutic vaccines for diseases in which CD8 cells play a crucial role. Clinicaltrials.gov NCT00261001

Skin vaccination aims at targeting epidermal and dermal antigen-presenting cells (APCs), indeed many subsets of different origin endowed with various functions populate the skin. The idea that the skin could represent a particularly potent site to induce adaptive and protective immune response emerged after the success of vaccinia virus vaccination by skin scarification. Recent advances have shown that multiple subsets of APCs coexist in the skin and participate in immunity to infectious diseases. Induction of an adaptive immune response depends on the initial recognition and capture of antigens by skin APCs and their transport to lymphoid organs. Innovative strategies of vaccination have thus been developed to target skin APCs for tailored immunity, hence this review will discuss recent insights into skin APC subsets characterization and how they can shape adaptive immune responses.

Obtaining a certain multi-functionality of cellular immunity for the control of infectious diseases is a burning question in immunology and in vaccine design. Early events, including antigen shuttling to secondary lymphoid organs and recruitment of innate immune cells for adaptive immune response, determine host responsiveness to antigens. However, the sequence of these events and their impact on the quality of the immune response remain to be elucidated. Here, we chose to study Modified Vaccinia virus Ankara (MVA) which is now replacing live Smallpox vaccines and is proposed as an attenuated vector for vaccination strategies against infectious diseases. We analyzed in vivo mechanisms triggered following intradermal (i.d.) and intramuscular (i.m.) Modified Vaccinia virus Ankara (MVA) administration. We demonstrated significant differences in the antigen shuttling to lymphoid organs by macrophages (MΦs), myeloid dendritic cells (DCs), and neutrophils (PMNs). MVA i.d. administration resulted in better antigen distribution and more sustained antigen-presenting cells (APCs) recruitment into draining lymph nodes than with i.m. administration. These APCs, which comprise both DCs and MΦs, were differentially involved in T cell priming and shaped remarkably the quality of cytokine-producing virus-specific T cells according to the entry route of MVA. This study improves our understanding of the mechanisms of antigen delivery and their consequences on the quality of immune responses and provides new insights for vaccine development.